perampanel and Brain-Injuries

Cardiac arrest has many implications for morbidity and mortality. Few interventions have been shown to improve return of spontaneous circulation (ROSC) and long-term outcomes after cardiac arrest. Ischemic-reperfusion injury upon achieving ROSC creates an imbalance between oxygen supply and demand. Multiple events occur in the postcardiac arrest period, including excitotoxicity, mitochondrial dysfunction, and oxidative stress and inflammation, all of which contribute to ongoing brain injury and cellular death. Given that complex pathophysiology underlies global brain hypoxic ischemia, neuroprotective strategies targeting multiple stages of the neuropathologic cascade should be considered as a means of mitigating secondary neuronal injury and improving neurologic outcomes and survival in cardiac arrest victims. In this review article, we discuss a number of different pharmacologic agents that may have a potential role in targeting these injurious pathways following cardiac arrest. Pharmacologic therapies most relevant for discussion currently include memantine, perampanel, magnesium, propofol, thiamine, methylene blue, vitamin C, vitamin E, coenzyme Q

Topics: Animals; Antioxidants; Brain Injuries; Brain Ischemia; Heart Arrest; Humans; Memantine; Neuroprotection; Neuroprotective Agents; Nitriles; Oxidative Stress; Pyridones; Thiamine

Subarachnoid hemorrhage (SAH) occurs most commonly after rupture of an aneurysm, resulting in high disability and mortality due to the absence of effective therapy. Its subsequent stage, early brain injury (EBI), promotes the sustainable development of injury in the brain and ultimately leads to poor prognosis. As a new antiepileptic drug, the effect of perampanel on EBI after SAH is unknown. Pyroptosis, a process of inflammatory programmed cell death, has been confirmed in most studies to play a substantial role in aggravating SAH-post EBI. Similarly, oxidative stress is closely involved in neuronal pyroptosis and the pathophysiological mechanism of SAH-post EBI, leading to a devastating outcome for SAH patients. Nonetheless, no studies have been conducted to determine whether perampanel reduces pyroptosis and oxidative stress in the context of SAH-induced EBI. Rat SAH model via endovascular perforation was constructed in this study, to assess the neuroprotective effect of perampanel on SAH-post EBI, and to clarify the possible molecular mechanism. By means of the neurological score, brain edema detection, FJB staining, immunofluorescence, WB, ELISA, and ROS assay, we found that perampanel can improve neuroscores and reduce brain edema and neuronal degeneration at 24 h after SAH; we also found that perampanel reduced oxidative stress, neuronal pyroptosis, and inhibition of the SIRT3-FOXO3α pathway at 24 h after SAH. When 3-TYP, an inhibitor of SIRT3, was administered, the effects of perampanel on the SIRT3-FOXO3a pathway, antioxidant stress, and neuronal pyroptosis were reversed. Taken together, our data indicate that perampanel attenuates oxidative stress and pyroptosis following subarachnoid hemorrhage via the SIRT3/FOXO3α pathway. This study highlights the application value of perampanel in subarachnoid hemorrhage and lays a foundation for clinical research and later transformation of perampanel in SAH.

Topics: Animals; Apoptosis; Brain Edema; Brain Injuries; Humans; Neuroprotective Agents; Oxidative Stress; Pyroptosis; Rats; Sirtuin 3; Subarachnoid Hemorrhage

Ischemic stroke is a leading cause of death and disability worldwide. Additionally, neonatal ischemia is a common cause of neonatal brain injury, resulting in cerebral palsy with subsequent learning disabilities and epilepsy. However, there is currently a lack of effective treatments available for patients with perinatal ischemic stroke. In this study, we investigated the effect of perampanel (PER)-loaded poly lactic-co-glycolic acid (PLGA) by targeting microglia in perinatal stroke.. After formation of focal ischemic stroke by photothrombosis in P7 rats, PER-loaded PLGA was injected intrathecally. Proinflammatory markers (TNF-α, IL-1β, IL-6, COX2, and iNOS) and M2 polarization markers (Ym1 and Arg1) were evaluated. We investigated whether PER increased M2 microglial polarization in vitro.. PER-loaded PLGA nanoparticles decreased the pro-inflammatory cytokines compared to the control group. Furthermore, they increased M2 polarization.. PER-loaded PLGA nanoparticles decreased the size of the infarct and increased motor function in a perinatal ischemic stroke rat model. Pro-inflammatory cytokines were also reduced compared to the control group. Finally, this development of a drug delivery system targeting microglia confirms the potential to develop new therapeutic agents for perinatal ischemic stroke.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Brain Ischemia; Cytokines; Ischemic Stroke; Microglia; Nitriles; Pyridones; Rats; Stroke

Spontaneous intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity due to the lack of effective therapies. The alpha‑amino‑3‑hydroxy‑5‑methyl‑4‑isoxazolepropionic acid receptor antagonist perampanel has been reported to alleviate early brain injury following subarachnoid hemorrhage and traumatic brain injury by reducing reactive oxygen species, apoptosis, autophagy, and necroptosis. Necroptosis is a caspase‑independent programmed cell death mechanism that serves a vital role in neuronal cell death following ICH. However, the precise role of necroptosis in perampanel‑mediated neuroprotection following ICH has not been confirmed. The present study aimed to investigate the neuroprotective effects and potential molecular mechanisms of perampanel in ICH‑induced early brain injury by regulating neural necroptosis in C57BL/6 mice and in a hemin‑induced neuron damage cell culture model. Mortality, neurological score, brain water content, and neuronal death were evaluated. The results demonstrated that perampanel treatment increased the survival rate and neurological score, and increased neuron survival. In addition, perampanel treatment downregulated the protein expression levels of receptor interacting serine/threonine kinase (RIP) 1, RIP3, and mixed lineage kinase domain like pseudokinase, and of the cytokines IL‑1β, IL‑6, TNF‑α, and NF‑κB. These results indicated that perampanel‑mediated inhibition of necroptosis and neuroinflammation ameliorated neuronal death

Topics: Administration, Oral; Animals; Brain Injuries; Cell Death; Cell Line; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Excitatory Amino Acid Antagonists; Hemin; Inflammation; Male; Mice, Inbred C57BL; Necroptosis; Neurons; Neuroprotective Agents; NF-kappa B; Nitriles; PTEN Phosphohydrolase; Pyridones; Receptors, Glutamate; Signal Transduction